Studies are proposed which aim to gain further information that is relevant to organ transplantation. An easily quantitated in vivo model, which allows accurate assay of rejection and employs transplantation of islets of Langerhans under the kidney capsule, will be employed for experiments to ascertain the cellular basis of rejection in a variety of immunogenetic disparities and sensitization states. Similar immunogenetic and sensitization situations will be studied in vitro in an attempt to evaluate the in vivo relevance of in vitro findings; studies will be performed in both mouse and man. Limiting dilution analyses, cloning of T (and possibly other) lymphocytes and functional characterization of these cells will be applied to both in vivo and in vitro models. Special emphasis will be given to the further characterization of the antigen driven, helper-cell independent cytotoxic T lymphocyte (HITc), which was described from our laboratories in both mouse and man and which appears to combine the attributes of helper T lymphocytes and conventional cytotoxic T lymphocytes. Neonatal-tolerance will be induced under a variety of circumstances to study further the phenomenon that we refer to as "composite determinant recognition" in which mice neonatally tolerized to (class I + class II) disparities demonstrate hyporeactivity in adult life to the class (I+II) disparity but are normally (or nearly so) reactive to the class I or the class II disparity presented alone. Studies of HLA restricted responses and signals required for activation, maturation and expansion of cytotoxic T lymphocytes are also proposed. The overall experimental plan is aimed at obtaining information that will allow successful organ transplantation of not only endocrine organs, such as islets, but hopefully other tissues as well.